Clinical studies support the therapeutic efficacy of adhesion molecule blockade (i.e. Natalizumab) in Crohn's disease (CD), yet the preclinical data that led to the targeting of specific adhesion molecules (i.e. integrin 14) originated from studies in animal models of colitis. However, sixty percent of patients with CD suffer from ileitis. Our work in novel murine models of ileitis (i.e. SAMP1/Yit, TNF?ARE) supports the novel concept that trafficking to the terminal ileum utilizes an overlapping yet distinct set of molecules, in part different from those that mediate traffic to the colon. This is illustrated by the lack of attenuation of ileitis seen after deletion of molecules critical for physiological trafficking or homing into the colon (i.e. CCR9, integrins 1427 or 1E27) in our model. Unexpectedly, TNF?ARE mice that lack L-selectin or the corresponding sulfotransferases responsible for its functional ligands, develop greatly attenuated disease. Thus our central hypothesis is that L-selectin is critically involved in the pathogenesis of murine ileitis. The TNF ?ARE model represents a unique tool to identify the mechanisms that underlie the attenuation of disease, mediated by L-selectin deficiency. We propose three specific aims to further explore this hypothesis. 1. Dissect the immunological effects of L-selectin deficiency in ileitis. 2. Assess the role of endothelial ligands on the attenuation of ileitis mediated by L-selectin deficiency. 3. Investigate hematopoietic determinants underlying attenuation of ileitis in L- selectin-deficient TNF ?ARE mice. Overall, these studies have the potential to open new perspectives on how T cells reach the small intestine, to induce and maintain ileitis. Given the similarities between the TNF a ARE model and CD, our findings may potentially lead to new therapeutic targets. PUBLIC HEALTH RELEVANCE: White blood cells normally traffic from the blood stream into the intestine, where they patrol for outside invaders. However in Crohn's disease (CD) this traffic is excessive, leading to intestinal damage and often incapacitating symptoms. Recent studies have shown that drugs that reduce excessive white blood cell traffic, like Natalizumab, are effective to treat Crohn's. Yet in rare occasions there are serious complications, as we do not fully understand how Natalizumab works. We have been studying a mouse strain that develops a chronic inflammatory disease of the small intestine, similar to CD and have noticed that when these mice lack L-selectin, a molecule that is involved in the traffic of white cells into the intestine, their disease is virtually absent. In these studies we will attempt to understand how by not having L-selectin these mice are protected from developing IBD. Understanding how white cells use these molecules to travel to the intestine may allow us to reduce white cell traffic and treat CD in an effective and safe manner.